DESCRIPTION: (applicant's abstract) It is well known that the expression of gangliosides is developmental regulated and these developmental changes correlate well with their putative functions in cellular recognition, interaction, and adhesion. The overall objective of this project is to gain a better understanding of the underlying mechanisms regulating ganglioside expression during brain development and in pathological conditions. The guiding principle is that these developmental changes in the expression of gangliosides is tightly regulated by their synthesis and degradation. To achieve this objective, we will continue to study the chemical structure, cellular distribution, and metabolism of gangliosides, and to elucidate their biological functions in the nervous system employing biochemical and molecular biological techniques. Since there are many stage-dependent gangliosides which play a critical role in early brain development, we will isolate them and characterize their structures. We will study the property, structure, cellular and subcellular localization of several glycosyltransferases, particularly those at key regulatory points of ganglioside biosynthetic pathways, by biochemical and immunocytochemical methods. Similar studies will be extended to brain sialidases which play a key role in ganglioside catabolism and may function as novel membrane- adhesion molecules. The regulatory mechanisms for the synthesis of gangliosides during brain development will be investigated by biochemical and molecular biological techniques at several levels, including transcriptional and posttranslational controls. We have discovered that the activities of several sialyltransferases are modulated by a novel phosphorylation/dephosphorylation mechanism and this observation will be further investigated. We have developed novel strategies to manipulate ganglioside synthesis and expression in cells by using antisense oligonucleotide and gene engineering techniques to study the function of gangliosides in relation to cellular differentiation and proliferation. An understanding of the molecular mechanisms underlying the differential expression of cell surface gangliosides should greatly enrich our knowledge in their functions in normal brain development as well as in neurological disorders that result in mental retardation.